The C—X—C chemokine receptor type 4 (CXCR4) plays a crucial role in physiological conditions, such as lymphopoiesis and bone marrow (BM) myelopoiesis, during embryogenesis. In postnatal life, CXCR4 and its ligand modulate homing of CD341 cells to the BM niches as well as lymphocytic trafficking CXCR4 has been shown to be mutated in patients with an inherited heterozygous autosomal dominant disease characterized by aberrantly functioning immunity, known as warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, because of the presence, among others, of an activating mutation of the CXCR4 gene, represented by the C1013G variant (Balabanian et al., 2005; Balabanian et al., 2008). Recent evidence supports the presence of CXCR4 somatic aberrations in Waldenström's macroglobulinemia (WM; lymphoplasmacytic lymphoma) (Hunter et al., 2014; Treon et al., 2014). The functional role of this variant in supporting progression of lymphoplasmacytic lymphoma and whether it is peculiar for WM or it occurs at an IgM monoclonal gammopathy of undetermined significance (MGUS) stage compared with other B-cell lymphoproliferative entities has not been previously described.
WM is a rare B-cell disorder with an incidence rate of about 3 cases per million people per year in the United States. About 1,000 to 1,500 people are diagnosed with WM each year in the U.S. Whole-genome sequencing has recently shed light on the molecular mechanisms that may contribute to the pathogenesis of this disease. Specifically, L265P/MYD88 has been described as a prevalent somatic mutation in WM patients (Treon et al., 2012). In vitro studies have demonstrated that the L265P/MYD88 variant may lead to increased tumor cell proliferation (Yang et al., 2013); this may be explained, at least in part, by MYD88-dependent activation of nuclear factor κB (NF-κB), a known signaling pathway that modulates tumor B-cell survival, growth, and resistance to therapy (Leleu et al., 2008). These observations are also consistent with previous findings that over-expression of the oncogenic microRNA-155 in clonal WM cells leads to activation of NF-κB in primary WM cells. Indeed, microRNA-155 loss-of-function studies led to inhibition of NF-κB and reduction of tumor growth in vitro and in vivo (Leleu et al., 2008; Roccaro et all, 2009). However, the MYD88 mutation did not predict progression or resistance to therapy in several published studies, indicating that other genetic alterations may be critical for tumor progression and dissemination to distant organs.
Among low-grade B-cell lymphomas, WM represents a lymphoplasmacytic subtype characterized by BM infiltration of lymphoplasmacytic cells and secretion of a serum monoclonal immunoglobulin M (IgM) protein that can lead to complications of hyperviscosity, bleeding and peripheral neuropathy (Ghobrial et al., 2003; Vijay and Gertz, 2007). The evidence for widespread involvement of the BM at the time of diagnosis implies cell trafficking of clonal B-cells into the BM. In this context, one of the main regulators of tumor B-cell homing to the BM is represented by CXCR4 through the interaction with its related ligand stromal derived factor-1 (SDF-1/CXCL12).
A preliminary report of whole genome sequencing has indicated that CXCR4 may be mutated in 29% (16/55) of patients with WM (Cao et al., 2012). The presence and role of the C1013/CXCR4 variant was therefore investigated in patients with WM and different B-cell lymphoproliferative disorders, aimed at defining the in vivo functional role of this variant in WM as well as the response of C1013G/CXCR4-associated WM patients to treatment with an anti-CXCR4 antibody.
Anti-CXCR4 monoclonal antibodies that exhibit therapeutic efficacy in treating cancer have previously been described in PCT Publication Nos. WO 2008/060367 and WO 2013/071068. The disclosures of both these applications are hereby incorporated in their entireties by reference into this application. A fully human monoclonal antibody, ulocuplumab (designated F7 in WO 2008/060367, and also previously designated BMS-936564 or MDX-1338, all four designations being used interchangeably herein), exhibited unexpectedly advantageous anti-tumor properties in preclinical studies with both solid tumors and hematologic cancers. Ulocuplumab is also currently undergoing Phase I clinical studies in patients with relapsed/refractory B-cell malignancies (NCT01120457; see Clinical Trials Website, http://www.clinicaltrials.gov).